EP2731969B1 - Antibodies to phosphorylated tau aggregates - Google Patents

Antibodies to phosphorylated tau aggregates Download PDF

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Publication number
EP2731969B1
EP2731969B1 EP12743696.2A EP12743696A EP2731969B1 EP 2731969 B1 EP2731969 B1 EP 2731969B1 EP 12743696 A EP12743696 A EP 12743696A EP 2731969 B1 EP2731969 B1 EP 2731969B1
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EP
European Patent Office
Prior art keywords
antibody
tau
seq
amino acid
acid sequence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP12743696.2A
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German (de)
English (en)
French (fr)
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EP2731969A1 (en
Inventor
Joris Winderickx
Eugeen Vanmechelen
Fred Van Leuven
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Katholieke Universiteit Leuven
Fujirebio Europe NV SA
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Katholieke Universiteit Leuven
Fujirebio Europe NV SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]

Definitions

  • Antibodies or antibody fragments may be further modified into an antibody-derived scaffold or antibody-like scaffolds that largely retains antigen-binding capacity of the antibody or antibody fragments from which it is derived.
  • antibody-derived scaffolds or antibody-like scaffolds are for domain antibody (dAb) that selectively or preferentially bind the same epitope as a natural antibody for instance dAb with fully human frameworks, for instance dAb fused to a human Fc domain or for instance nanobodies engineered in a molecule that has an IgG-like circulating half-life in humans or antibody fragments with retained antigen-binding capacity or domain antibody with active scaffolds for controlled and cell delivery.
  • dAb domain antibody
  • a Fab' fragment is, however, structurally equivalent to Fab in that both are antigen-binding fragments which comprise the variable regions of a heavy chain and light chain, which serve as a single antigen-binding domain.
  • an antigen-binding fragment comprising the variable regions of a heavy chain and light chain which serve as a single antigen-binding domain, and which is equivalent to that obtained by papain digestion, is referred to as a "Fab-like antibody", even when it is not identical to an antibody fragment produced by protease digestion.
  • Fab'-SH is Fab' with one or more cysteine residues having free thiol groups in its constant region.
  • a F(ab') fragment is produced by cleaving the disulfide bond between the cysteine residues in the hinge region of F(ab')2.
  • Other chemically crosslinked antibody fragments are also known to those skilled in the art.
  • the antibody or antibody fragment of present specification may comprise at least one CDR triplet selected from the group consisting of
  • the antibody or antibody fragment of present specification may comprise at least one CDR triplet selected from the group consisting of
  • the antibody or antibody fragment of present specification may comprise at least one variable domain having an amino acid sequence selected from the group consisting of SEQ ID NO. 25 and 26 or an amino acid sequence which has at least 80 % identity to an amino acid sequence selected from the group consisting of SEQ ID NO. 25 and 26.
  • percentage identity or “% identity” between two or more amino acid sequences or two or more nucleotide sequences refers to the ratio, expressed in %, of :
  • the carrier reagent is a lipid liposome or the like that can complex with the tau antibody, tau antibody-like scaffold or tau antibody fragment of present invention and promote the delivery of the protein into the cell.
  • the protein encapsulated in the formulation binds to the negatively vehicle for delivery ( O. Zelphati et al., J. Bio. Chem., 276, 35103-19 (2001 )).
  • Products available commercially can be used, such as BioPORTER (Gene Therapy Systems), or ProVectin (Imgenex, San Diego, Calif.).
  • Oil-in-water emulsions include MF59 (see WO 90/14837 to Van Nest et al. , which is hereby incorporated by reference in its entirety), containing 5% Squalene, 0.5% Tween 80, and 0.5% Span 85 (optionally containing various amounts of MTP-PE) formulated into submicron particles using a micro fluidizer; SAF, containing 10% Squalene, 0.4% Tween 80, 5% pluronic-blocked polymer L121, and thr-MDP, either microfluidized into a submicron emulsion or vortexed to generate a larger particle size emulsion; and the RibiTM adjuvant system (RAS) (Ribi ImmunoChem, Hamilton, Mont.) containing 2% squalene, 0.2% Tween 80, and one or more bacterial cell wall components selected from the group consisting of monophosphoryllipid A (MPLA), trehalose dimycolate (TDM), and cell wall skeleton (CWS
  • antibodies and antibody fragments of the invention can be obtained using various phage display methods known in the art.
  • phage display methods functional antibody domains are displayed on the surface of phage particles which carry the polynucleotide sequences encoding them.
  • phage can be utilized to display epitope-binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine).
  • Phage expressing an epitope-binding domain that binds the antigen of interest can be selected or identified with antigen, e.g., using labeled antigen bound or captured to a solid surface or bead.
  • tauopathy or “tau-associated disease” encompasses any neurodegenerative disease that involves the pathological aggregation of the microtubule protein tau within the brain. Accordingly, in addition to both familial and sporadic Alzheimer's disease, other tauopathies that can be treated using the methods of the present invention specification include, without limitation, frontotemporal dementia, parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration, Pick's disease, progressive subcortical gliosis, tangle only dementia, diffuse neurofibrillary tangles with calcification, argyrophilic grain dementia, amyotrophic lateral sclerosis parkinsonism-dementia complex, dementia pugilistica, Down syndrome, Gerstmann-Straussler-Scheinker disease, Hallerworden-Spatzdisease, inclusion body myositis, Creutzfeld-Jakob disease, multiple system atrop
  • the antibody of the present invention can be used in a method for monitoring residual disease, such as Alzheimer's disease, following treatment with a vaccine composition.
  • Monitoring minimal residual disease in an individual following treatment with a vaccine composition may be achieved by detecting the immunospecific binding of a monoclonal antibody or a functional fragment thereof to an epitope of the tau protein in a sample or in situ, which includes bringing the sample or a specific body part or body area suspected to contain the tau antigen into contact with an antibody which binds an epitope of the tau protein, allowing the antibody to bind to the tau antigen to form an immunological complex, detecting the formation of the immunological complex and correlating the presence or absence of the immunological complex with the presence or absence of the tau antigen in the sample or specific body part or body area, optionally comparing the amount of said immunological complex to a normal control value, wherein an increase in the amount of said aggregate compared to a normal control value indicates that said individual is still suffering from a minimal residual disease.
  • the sample to be tested is added to the plates.
  • purified aggregated tau is added to separate wells of the ELISA plate.
  • known amounts of purified aggregated tau are added to separate wells of the ELISA plate.
  • bound aggregated tau is detected using a secondary antibody capable of binding to aggregated tau. This can be an antibody which recognizes total tau, such as tau-5 or HT-7, a phosphorylation-specific anti-tau antibody, such as AT270, or a second aggregated tau-specific antibody, or a combination of two or more such antibodies.
  • immunodetection of aggregated tau can be performed in a bead-based assay like the Luminex® xMAP® technology, allowing for simultaneous multiparametric analysis like described for the INNO-BIA AlzBio3 (Olsson et al., 2005).
  • Aggregated tau can be detected in a majority x % of samples of patients suffering from a tauopathy, but only in a minority y % of samples from control subjects.
  • the sensitivity of a diagnostic test for a tauopathy, based upon the aggregated tau as a disease marker is then x/100, while the specificity of the diagnostic test is then (100-y)/100.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Urology & Nephrology (AREA)
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  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Physics & Mathematics (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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EP12743696.2A 2011-07-14 2012-07-16 Antibodies to phosphorylated tau aggregates Active EP2731969B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1112056.5A GB201112056D0 (en) 2011-07-14 2011-07-14 Antibodies
PCT/EP2012/063924 WO2013007839A1 (en) 2011-07-14 2012-07-16 Antibodies to phosphorylated tau aggregates

Publications (2)

Publication Number Publication Date
EP2731969A1 EP2731969A1 (en) 2014-05-21
EP2731969B1 true EP2731969B1 (en) 2018-10-17

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US (1) US9447179B2 (enExample)
EP (1) EP2731969B1 (enExample)
JP (1) JP6168364B2 (enExample)
AU (1) AU2012282402B2 (enExample)
GB (1) GB201112056D0 (enExample)
WO (1) WO2013007839A1 (enExample)

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AU2012282402B2 (en) 2017-03-09
US9447179B2 (en) 2016-09-20
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GB201112056D0 (en) 2011-08-31
EP2731969A1 (en) 2014-05-21
US20140161875A1 (en) 2014-06-12
AU2012282402A1 (en) 2014-01-30
JP6168364B2 (ja) 2017-07-26
JP2014523742A (ja) 2014-09-18
WO2013007839A1 (en) 2013-01-17

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